Abstract 3270: The XernaTM TME Panel potentially predicts response to a combination of the TLR9 agonist vidutolimod and PD-1 inhibitor pembrolizumab in metastatic melanomas with prior anti-PD-1 treatment
Authors: Mark T. Uhlik, Daniel Pointing, Luka Ausec, Miha Stajdohar, Robert Cvitkovic, Matjaz Zganec, Seema Iyer, Hong Liu, Art Krieg, Laura Benjamin
Journal: Cancer Research (2023)

Abstract Background: Few therapeutic options exist for anti-PD-1 refractory, metastatic melanoma patients, and today’s biomarkers are insufficient to aid in defining who should receive potential combinatorial immunotherapies. Results from a phase Ib, multicenter study (NCT02680184) showed that a combination of vidutolimod and pembrolizumab provided a best overall response of 23.5% in patients with metastatic or unresectable cutaneous melanoma who had received prior anti-PD-1 therapy. The Xerna™ TME Panel consists of an artificial neural net that utilizes the expression of ~100 genes involved in angiogenesis and tumor immune biologies to classify patient samples into one of four tumor microenvironment (TME) biomarker subtypes: Angiogenesis (A), Immune Active (IA), Immune Desert (ID), or Immune Suppressed (IS). We hypothesized that the IS subtype is predictive of vidutolimod + pembrolizumab benefit in this cohort compared to the other TME subtypes (A, IA, and ID). Methods: Total RNASeq was performed on FFPE biopsies collected from a subset of patients prior to therapy (N=38) and 2 weeks post-initiation of therapy (N=10). Gene expression data was analyzed using the Xerna TME Panel algorithm to assign a TME subtype. Correlational analyses between TME subtypes, response to therapy, and other hallmark gene signatures were performed. Results: Overall response rate in the pretreatment cohort available for biomarker analysis was 26%, comparable to the entire vidutolimod/pembrolizumab arm. The cohort had a skewed distribution of TME subtypes with high prevalence of IS (34%) and ID (45%), indicative of immune therapy-refractory biologies. An overall response of 54% was observed in the IS subtype, compared with 12% in the other subtypes combined. Comparison with other “hallmark” gene signatures confirmed enrichment of immune and angiogenesis biologies in the IS subtype, but none of these individual hallmark signatures were found to differentiate between responders and non-responders. The Xerna TME Panel demonstrated superior classification performance across all criteria compared to a baseline classifier, including accuracy (0.76 vs. 0.62), sensitivity (0.70 vs. 0.27) and specificity (0.79 vs. 0.74). Among matched post-treatment samples, 70% revealed a change in TME subtype compared to their pre-treatment status. Three of the post-treatment samples represented changes from an immune-low subtype to an immune-high subtype, including one complete responder with a pre-treatment ID that changed to IA while on therapy, illustrating how the TME Panel may be used to interpret the mechanism of drug response. Conclusions: The Xerna TME Panel shows potential activity as a predictive and pharmacodynamic biomarker for the combination of vidutolimod and pembrolizumab in anti-PD-1 refractory melanoma patients. Citation Format: Mark T. Uhlik, Daniel Pointing, Luka Ausec, Miha Stajdohar, Robert Cvitkovic, Matjaz Zganec, Seema Iyer, Hong Liu, Art Krieg, Laura Benjamin. The XernaTM TME Panel potentially predicts response to a combination of the TLR9 agonist vidutolimod and PD-1 inhibitor pembrolizumab in metastatic melanomas with prior anti-PD-1 treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3270.